Mari L. Shinohara
Immune responses against pathogens are essential for host protection, but excessive and uncontrolled immune reactions can lead to autoimmunity. How does our immune system keep the balance fine-tuned? This is a central question being asked in my laboratory.
The immune system needs to detect pathogens quickly and effectively. This is performed by the innate immune system, which includes cells such as macrophages and dendritic cells (DCs). Pathogens are recognized by pattern recognition receptors (PRRs) and may be cleared in the innate immune system. However, when pathogens cannot be eliminated by innate immunity, the adaptive immune system participates by exploiting the ability of T cells and B cells. The two immune systems work together not only to clear pathogens effectively but also to avoid collateral damages by our own immune responses.
In my lab, we use mouse models for infectious and autoimmune diseases to understand the cellular and molecular mechanisms of; pathogen recognition by PRRs in macrophages and DCs, initiation of inflammatory responses in the innate immune system, and the impact of innate immune inflammation on the development and regulation of T cell-mediated adaptive immune responses.
Several projects are ongoing in the lab. They are to study (1) the roles of PRR in EAE (an animal model of multiple sclerosis), (2) the interplay between immune cells and CNS (central nervous system)-resident cells during EAE and fungal infection, (3) protective and pathogenic mechanisms of immune cells in the lung during fungal infection and inflammation, and (4) the roles of a protein termed osteopontin (OPN), as both secreted (sOPN) and intracellular (iOPN) isoforms, in regulation of immune responses . Although we are very active in EAE to study autoimmunity, other mouse models, such as graft-versus-host disease (GvHD) is ongoing. Cell types we study are mainly DCs, macrophages, neutrophils, and T cells.
Inoue, Makoto, Kristi L. Williams, Michael D. Gunn, and Mari L. Shinohara. “NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis.” Proc Natl Acad Sci U S A 109, no. 26 (June 26, 2012): 10480–85. https://doi.org/10.1073/pnas.1201836109.
Inoue, Makoto, Kristi L. Williams, Timothy Oliver, Peter Vandenabeele, Jayant V. Rajan, Edward A. Miao, and Mari L. Shinohara. “Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome.” Sci Signal 5, no. 225 (May 22, 2012): ra38. https://doi.org/10.1126/scisignal.2002767.
Michalek, Ryan D., Valerie A. Gerriets, Amanda G. Nichols, Makoto Inoue, Dmitri Kazmin, Ching-Yi Chang, Mary A. Dwyer, et al. “Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation.” Proc Natl Acad Sci U S A 108, no. 45 (November 8, 2011): 18348–53. https://doi.org/10.1073/pnas.1108856108.
Inoue, Makoto, Yasuhiro Moriwaki, Tomohiro Arikawa, Yu-Hsun Chen, Young Joo Oh, Timothy Oliver, and Mari L. Shinohara. “Cutting edge: critical role of intracellular osteopontin in antifungal innate immune responses.” J Immunol 186, no. 1 (January 1, 2011): 19–23. https://doi.org/10.4049/jimmunol.1002735.
Shinohara, Mari L., June-Ho Kim, Virgilio A. Garcia, and Harvey Cantor. “Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin.” Immunity 29, no. 1 (July 18, 2008): 68–78. https://doi.org/10.1016/j.immuni.2008.05.008.
Shinohara, Mari L., Hye-Jung Kim, June-Ho Kim, Virgilio A. Garcia, and Harvey Cantor. “Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells.” Proc Natl Acad Sci U S A 105, no. 20 (May 20, 2008): 7235–39. https://doi.org/10.1073/pnas.0802301105.
Shinohara, M. L., and H. Cantor. “Innate immune mechanisms that promote development of effector and regulatory CD4 lineages in EAE (Experimental Autoimmune Encephalomyelitis).” In Journal of Neuroimmunology, 178:34–34, 2006.
Shinohara, Mari L., Linrong Lu, Jing Bu, Miriam B. F. Werneck, Koichi S. Kobayashi, Laurie H. Glimcher, and Harvey Cantor. “Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells.” Nat Immunol 7, no. 5 (May 2006): 498–506. https://doi.org/10.1038/ni1327.
SHINOHARA, M. L. “Osteopontin expression is essential for interferon-α production by plasmacytoid dendritic cells.” Nat. Immunol. 7 (2006): 498–506.